1. Field of the Invention
The invention relates to a development in the field of sustained release systems of active substances, more particularly in the area of medicinal and/or biological valuable materials from a carrier material.
2. Statement of Related Art
Combination materials of this kind are the subject matter of numerous recent investigations and printed publications in both the fields of pharmaceutical auxiliary materials and of biological preparations, for example crop protection chemicals. They are designated by terms such as retard systems, depot or slow release materials, respectively, or quite generally as mixtures of active substances providing a sustained release of the valuable materials.
Depot materials of this kind usually consist of a carrier with or without any activity of its own, in which an active substance, the release of which is to be sustained, has been incorporated. In recent literature particular attention has been given to polymer compounds based on polyesters of lower hydroxycarboxylic acids as carrier materials, more specifically those having from 2 to 6 carbon atoms in the hydroxycarboxylic acid molecule. Carrier materials of this kind are prone to undergo hydrolysis and are subject to biological degradation mechanisms. The corresponding polyesters derived from glycolic acid, lactic acid and/or hydroxybutyric acid having restricted molecular weights are of particular importance.
Among the more recent pertinent literature, reference may be made, for example, to U.S. Pat. No. 4,011,312, which discloses solid formulations of copolyesters of glycolic acid and lactic acid, having molecular weights of below 2,000, as a carrier material in admixture with antibiotically active substances such as tetracycline, neomycin and other antibiotics for the treatment of bovine mastitis at room temperature or body temperature. The preparation of lower molecular weight poly(.beta.-hydroxybutyrate, PHB) and the use thereof as a solid carrier material for the formulation of sustained release tablets containing a pharmaceutically active substance has been described in "Die angewandte makromolekulare Chemie" 161 (1988), 1-8 (No. 2604). Upon the investigation of the release kinetics it has been shown, in the case presented here, that the amount of the active ingredient released is highly dependent on the molecular weight of the PHB fraction, the retardation in the release of the active substance being increased with the decrease in the molecular weight.
Numerous investigations deal with the use of resorbable polyesters based on glycolic acid/lactic acid as a carrier material for the sustained release of the active substance when used in combination with medicinal valuable materials, crop protection agents and the like. Reference may be made, e.g., to D. L. Wiese et al. in: "Drug Carriers in Medicine", Academic Press, London 1979, pp. 237-270, and to the literature quoted therein re retard forms of drugs; R. L. Kronenthal, Polym. Sci. Technol. 1975, 8 (Polym. Med. Surg.), 119-137.
The manner of the release of the active substance is affected, on the one hand, by the interaction between the active substance and the carrier material while, on the other hand, it is highly dependent on the structure and the properties of the usually polymeric carrier material. For example, the active substance may be micro-encapsulated in the polyesters of the type mentioned, it may be embedded in the polymer matrix, or it may be bonded to the terminal groups.
Thus, the release of the active ingredient proceeds via different mechanisms depending on the formulation. In the case of encapsulated active substances the diffusion of the active substances through micropores in the envelope plays an important role. If the active substances are dispersed or dissolved in a solid polymer matrix, the release of the active ingredients is governed by the diffusion through the matrix, by the hydrolytic erosion of the matrix or by a combination of these parameters. Nevertheless, the usability of such a depot system includes considerations on how the concerned substance mixture is to be handled. The depot material should be storage-stable under normal conditions of storage, should be sufficiently solid and dispensable in portions, should not undergo clogging during the conditions of manufacture, transportation and storage, and should exhibit a sufficient stability to the presence of moisture and the like.
In consideration of these numerous requirements which are difficult to reconcile with each other, it is not unusual that to date, use of retard systems and/or depot materials based on body-resorbable polyesters of lower hydroxycarboxylic acids have not been used in practice.